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Title: Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas
Authors: Hirpara, J.L 
Loh, T 
Ng, S.B 
Chng, W.J 
Pervaiz, S 
Keywords: apoptotic protease activating factor 1
reactive oxygen metabolite
antineoplastic agent
APAF1 protein, human
apoptotic protease activating factor 1
CASP3 protein, human
caspase 3
reactive oxygen metabolite
cell level
controlled study
diffuse large B cell lymphoma
human cell
human tissue
lipid raft
primary cell
protein expression
protein localization
protein secretion
T cell lymphoma
diffuse large B cell lymphoma
drug effects
drug resistance
Jurkat cell line
lipid peroxidation
membrane microdomain
signal transduction
tumor cell line
Antineoplastic Agents
Apoptotic Protease-Activating Factor 1
Caspase 3
Cell Line, Tumor
Drug Resistance, Neoplasm
Jurkat Cells
Lipid Peroxidation
Lymphoma, Large B-Cell, Diffuse
Membrane Microdomains
Reactive Oxygen Species
Signal Transduction
Issue Date: 2016
Publisher: Impact Journals LLC
Citation: Hirpara, J.L, Loh, T, Ng, S.B, Chng, W.J, Pervaiz, S (2016). Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas. Oncotarget 7 (51) : 83964-83975. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Resistance to chemotherapy remains a challenge in the clinical management of diffuse B cell lymphomas despite aggressive chemotherapy such as CHOP and monoclonal CD20. Here we provide evidence that the apoptosome adaptor protein, Apaf-1, is mislocalized in primary cells derived from patients with diffuse large B cell lymphomas (DLBCL). Whereas, the total expression of Apaf-1 did not change, its subcellular localization was significantly different in DLBCL, compared to T cell lymphomas as well as cells derived from reactive lymphadenopathy biopsies. As expected, Apaf-1 was detected in the cytosolic fractions of non-B cell lymphomas and non-cancerous tissues; however, in B cell derived lymphomas the protein was detected in membrane raft sub-domains rather than the cytosol. Disruption of lipid raft structures resulted in the redistribution of Apaf-1 to the cytosol and restored apoptosis sensitivity of DLBCL. Furthermore, we identified novel small molecule compounds that target DLBCL by promoting Apaf-1 release form lipid rafts via mechanisms that involve an increase in intracellular reactive oxygen species production. Taken together, our results implicate Apaf-1 mislocalization as a potential diagnostic and prognostic marker for DLBCL, and provide a novel therapeutic strategy for circumventing the drug refractory nature of this sub-class of B cell lymphoma.
Source Title: Oncotarget
ISSN: 1949-2553
DOI: 10.18632/oncotarget.13336
Rights: Attribution 4.0 International
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